This invention relates to pharmaceutical combinations of a xcex3-aminobutyric acid (GABA) agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug, kits containing such combinations and methods of using such combinations to treat mammals, including humans, suffering from diabetic complications such as, inter alia, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts or foot ulcers. This invention also relates to additive and synergistic combinations of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and an ARI, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug, whereby those additive and synergistic combinations are useful in treating mammals, including humans, suffering from diabetic complications such as, inter alia, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts or foot ulcers.
GABA is the major inhibitory neurotransmitter in the mammalian central nervous system. Its receptors have been divided into two main types. The more prominent GABA receptor subtype, the GABAA receptor, is a ligand-gated Clxe2x88x92 ion channel that is opened after release of GABA from presynaptic neurons. A second receptor, the GABAB receptor, is a member of the G protein-coupled receptor family coupled both to biochemical pathways and to regulation of ion channels. (Goodman and Gilman""s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y., 9th Edition, (1996).
By gating negative chloride (Clxe2x88x92) ions into the interior of cells, GABA inhibits the presynaptic release of neurotransmitter due to a positive voltage polarization pulse. Such inhibition is extremely common: GABA receptors can be found in 60-80% of central nervous system neurons. Subtypes of GABA receptors can be activated by the mushroom toxin muscimol (at GABAA) as well as the antispasmodic amino acid baclofen (GABAB). These compounds directly mimic the action of GABA at the receptor. Allosteric facilitation of GABA receptors occurs at several distinct sites; the compounds which bind there are used as sedatives and anxiolytics. Progabide is a prodrug which decomposes to GABA after crossing the blood/brain barrier into the central nervous system. Vigabatrin (gamma-vinyl-GABA) promotes binding of GABA by inhibiting GABA-aminotransferase (GABA-T), the enzyme responsible for degrading GABA in the synapse.
GABA agonists well known in the art include muscimol, progabide, riluzole, baclofen, gabapentin (Neurontin(copyright)), vigabatrin, valproic acid, tiagabine (Gabitril(copyright)), lamotrigine (Lamictal(copyright)), pregabalin, phenytoin (Dilantin(copyright)), carbamazepine (Tegretol(copyright)), topiramate (Topamax(copyright)) and analogs, derivatives, prodrugs and pharmaceutically acceptable salts of those GABA agonists. It will be recognized by those skilled in the art in light of this disclosure that other GABA agonists are also useful in the combinations, pharmaceutical compositions, methods and kits of this invention. GABA agonists have been disclosed to be useful in antiseizure therapy for central nervous system disorders such as epilepsy, Huntington""s chorea, cerebral ischemia, Parkinson""s disease, tardive dyskinesia and spasticity. GABA agonists have also been disclosed to be useful as antidepressants, anxiolytics and antipsychotics. Further, GABA agonists have been disclosed to have utility in the treatment of pain.
Aldose reductase inhibitors function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses, such as glucose and galactose, to the corresponding polyols, such as sorbitol and galactitol, in humans and other animals. In this way, unwanted accumulations of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, peripheral nervous cord and kidneys of various diabetic subjects are prevented or reduced. Accordingly, aldose reductase inhibitors are of therapeutic value for controlling certain diabetic complications, e.g., diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy.
This invention is directed to pharmaceutical compositions comprising:
a. an amount of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug;
b. an amount of an ARI, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug; and, optionally,
c. a pharmaceutically acceptable vehicle, carrier or diluent.
This invention is also directed to kits for achieving a therapeutic effect in a mammal comprising:
a. an amount of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and a pharmaceutically acceptable vehicle, carrier or diluent in a first unit dosage form;
b. an amount of an ARI, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a pharmaceutically acceptable vehicle, carrier or diluent in a second unit dosage form; and
c. a container.
This invention is also directed to methods for treating a mammal in need of therapeutic treatment comprising administering to said mammal
(a) an amount of a first compound, said first compound being a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug; and
(b) an amount of a second compound, said second compound being an ARI, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug;
wherein said first compound and said second compound are each optionally and independently administered together with a pharmaceutically acceptable vehicle, carrier or diluent.
This invention is also directed to methods for treating a mammal in need of therapeutic treatment comprising administering to said mammal a pharmaceutical composition comprising
(a) an amount of a first compound, said first compound being a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug; and
(b) an amount of a second compound, said second compound being an ARI, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug; and, optionally,
(c) a pharmaceutically acceptable vehicle, carrier or diluent.
The methods of this invention include therapeutic treatment of diabetic complications. Diabetic complications which may be treated by the methods of this invention include, inter alia, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts and foot ulcers. Humans are especially preferred mammals which are treated by the methods of this invention.
Preferred ARIs for use in the combinations, pharmaceutical compositions, methods and kits of this invention include fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, prodrugs thereof and pharmaceutically acceptable salts of said ARIs and said prodrugs. It is especially preferred that said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug.
Preferred GABA agonists for use in the combinations, pharmaceutical compositions, methods and kits of this invention include: muscimol, progabide, riluzole, baclofen, gabapentin (Neurontin(copyright)), vigabatrin, valproic acid, tiagabine (Gabitril(copyright)), lamotrigine (Lamictal(copyright)), pregabalin, phenytoin (Dilantin(copyright)), carbamazepine (Tegretol(copyright)), topiramate (Topamax(copyright)), prodrugs thereof and pharmaceutically acceptable salts of said GABA agonists and said prodrugs.
More preferred GABA agonists for use in the combinations, pharmaceutical compositions, methods and kits of this invention include gabapentin, tiagabine, lamotrigine, phenytoin, carbamazepine, topiramate, pregabalin, prodrugs thereof and pharmaceutically acceptable salts of said GABA agonists and said prodrugs.
A particularly preferred GABA agonist for use in the combinations, pharmaceutical compositions, methods and kits of this invention is pregabalin, a prodrug thereof or a pharmaceutically acceptable salt of said pregabalin or said prodrug.
Another particularly preferred GABA agonist for use in the combinations, pharmaceutical compositions, methods and kits of this invention is gabapentin, a prodrug thereof or a pharmaceutically acceptable salt of said gabapentin or said prodrug.